Is CTLA4 p.Pro63Arg (c.188C>G) pathogenic?

CTLA4 p.Pro63Arg (c.188C>G) is classified Uncertain significance in CTLA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.099); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTLA4 p.Pro63Arg (c.188C>G)?

CTLA4 p.Pro63Arg (c.188C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CTLA4 p.Pro63Arg (c.188C>G) in the general population?

CTLA4 p.Pro63Arg (c.188C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CTLA4 p.Pro63Arg (c.188C>G)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

CTLA4 p.Pro63Arg

c.188C>G · VCV4007949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP -2.9, phastCons 0.01
Regional constraint	o/e 0.66	unconstrained · MANE · 2,198 bp · p 3.2e-07 · regional, not allelic
Overall
CADD	13.99	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,892 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CTLA4
Protein: p.Pro63Arg
Coding: c.188C>G
MANE Select: NM_005214
Type: single nucleotide variant
Location: chr2:203870664 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB
Residue 63: a disulfide bond; an α-helix; the ig-like v-type domain

Full CTLA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTLA4 p.Pro63Leu Uncertain significance ★ ⚠ same residue
CTLA4 p.Pro63Ser Uncertain significance ★ ⚠ same residue
CTLA4 p.Gly146Arg Pathogenic/Likely pathogenic ★★ same condition
CTLA4 p.Leu163Phe Uncertain significance ★★ ⚠ same condition
CTLA4 p.Met90Arg Uncertain significance ★★ ⚠ same condition
CTLA4 p.Ser55Asn Uncertain significance ★★ ⚠ same condition
CTLA4 p.Glu155Ala Uncertain significance ★ ⚠ same condition
CTLA4 p.Glu155Asp Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ctla4-p-pro63arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown